Recent developments in our understanding of how platelet-derived growth factor (PDGF) and its receptors contribute to proliferative vitreoretinopathy.

Abstract

Proliferative vitreoretinopathy, a disease process occurring in the setting of a rhegmatogenous retinal detachment, is thought to develop as a result of exposure of retinal cells to vitreous. Vitreous contains many growth factors, and platelet-derived growth factor (PDGF) has been considered a major contributor to PVR. Evaluation of both PDGF and PDGF receptors (PDGFRs) as potential therapeutic targets in the context of a rabbit model of PVR revealed that PDGFR-based approaches protected from PVR, whereas neutralizing PDGFs was a much less effective strategy. The basis for these observations appears to reflect that fact that the PDGFR could be activated by a wide spectrum of vitreal agents that are outside of the PDGF family. Furthermore, blocking signaling events by which the non-PDGFs indirectly activated PDGF alpha receptor (PDGFRalpha) protected rabbits from developing PVR. These studies demonstrate that the best therapeutic targets for PVR are not PDGFs, but PDGFRalpha and certain signaling events required for indirectly activating PDGFRalpha.

The break in the retinal exposes cells within the retina and beneath it to the various agents within vitreous. These agents include growth factors and cytokines that promote cellular responses intrinsic to PVR such as migration, survival, proliferation and extracellular matrix production. The consequence of such cellular responses is the formation of an epiretinal membrane. Growth factors and cytokines within vitreous can stimulate cells within this epiretinal membrane to contract and thereby detach the retina.

PDGF-C is secreted in a biologically inactive (latent) form. Proteolytic cleavage of the CUB domain permits the core domain to bind and activate PDGFRs. The diagram shows an autocrine relationship between cells that produce and respond to PDGF; this appears to be the case for mesenchymal cells (; ). PDGF-C is also likely to activate cells in a paracrine manner.

There are two receptor subunits, and they are either homo-, or heterodimerized by PDGF to form a functional PDGFR. PDGF-B is the universal ligand. PDGF-AB and PDGF-C assemble and activate both PDGFRα and PDGFRαβ. PDGF-D activates PDGFRβ, and under certain circumstances PDGFRαβ. PDGF-A is the most selective member of the PDGF family and activates PDGFRα exclusively. There is no evidence that PDGF-AC, PDGF-BC, PDGF-AD, PDGF-BD or PDGF-CD exist.